Treatment Induced Changes in the Breast: Diagnosis and Staging of ...

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The key tasks in evaluating the breast excision specimen (lumpectomy or mastectomy) following NACT are: -determining residual tumor size -distinguishing treatment effect on benign breast from tumor -detecting nodal metastases in the presence of treatment effect -evaluating margin status for occult single tumor cells Defining Response to Chemotherapy The World Health Organization and International Union Against Cancer have defined criteria for evaluating response to systemic therapy in general: Complete response (CR): complete absence of detectable disease Partial response (PR): >50% reduction in maximal dimension of tumor Progressive disease (PD): increase in tumor size by more than 25% Stable disease (SD): no increase in tumor size more than 25% No response (NR): scenarios that do not fulfill any of the above criteria Response can be evaluated clinically, in which case the nomenclature is prefixed by the letter “c”. For example, cCR indicates a complete disappearance of tumor by clinical exam. Response can also be evaluated pathologically at time of surgery. For example, pCR indicates that no residual tumor is found in the specimen. pPR indicates that the residual tumor found in the specimen is more than 50% smaller than the pre-treatment size. This nomenclature is predominantly used clinically. As long as the residual tumor size (or its absence) is indicated in surgical pathology reports, the pathologist need not incorporate this vocabulary into the pathology report. Efficacy of NACT The NSABP-B18 trial is one of the largest prospective randomized trials to evaluate NACT in breast cancer. 608 patients were randomized to receive a pre-operative course of four cycles of AC (doxorubicin and cyclophosphamide) and 626 patients were randomized to receive post-operative treatment by the same chemotherapy. Patients were followed for 9 years. Overall, 80% of tumors showed at least a clinical partial response and clinical complete response in 36%; among these with cCR, 38% had pCR. 13% had both cCR and pCR while 7% had pCR without cCR. Lymph node metastases were also fewer in the NACT group compared to standard post-operative adjuvant treatment. From a clinical management perspective, more patients were able to undergo lumpectomy following NACT, a benefit that extended to patients whose tumors were initially clinically measured >5 cm. Overall survival and disease free survival was no different, however, between pre and post-operatively treated patients. Among neoadjuvant treated patients, better overall survival and disease free survival occurred in those with both a clinical and pathologic complete response. Poor nuclear grade in pre-treatment biopsy was associated with pCR (26% achieve pCR) versus good nuclear grade (14%). A recent meta-analysis of the handful of well-designed clinical trials confirmed this finding that overall survival is the same as standard adjuvant therapy. The main benefit is conversion to breast conservation in a subset of patients as well as identifying non-responders to chemotherapy. Gross Pathologic Changes Following NACT Stromal fibrosis and a wound-healing type of response are common changes in breast tumors that respond to NACT. This can sometimes, but not always be appreciated grossly. If a pathologic complete response occurs, the gross appearance may be either unremarkable or fibrotic at the site of the original tumor bed. If microscopic residual tumor exists, there might not be any gross finding other than fibrosis. We have encountered cases of apparent complete clinical response in which there no gross findings but occult tumor cells were widely scattered throughout the breast.
Sampling Recommendations for NACT breast specimens Gross estimation of residual tumor size can be misleading because of stromal fibrosis. Both overestimates and underestimates of residual tumor size can occur, therefore, careful correlation with findings on histologic slides is important. Reconstruction of tumor size based on slide findings is more accurate in our experience (see below). It is important to know the pre-chemotherapy estimate of tumor size. Tissue from across at least that dimension should be sampled from the mastectomy regardless of whether gross pathology is present or not. For example, if the pre-chemotherapy tumor was 5 cm but the gross residual tumor is 2 cm, tissue should be sampled from at least 5 cm surrounding the center of the residual mass. In fact, because clinical/radiologic size estimates can be under-estimates, we would extend the sampling to beyond a 5 cm size just in case microscopic tumor was present beyond the clinically estimated boundaries. Heavy sampling of margins is also advised, regardless of whether the gross appearance is suspicious or not. Measuring Residual Tumor Following NACT Tumors do not necessarily shrink concentrically from the outside inwardly or vice versa; tumor regression can be patchy and irregular. Residual tumor may be present in one of several patterns: A dominant mass (usually grossly visible) Scattered nodules amongst altered stroma (usually grossly visible) Occult microscopic foci scattered amongst altered stroma (not grossly visible) Rare scattered single cells (not grossly visible. This variability causes difficulty not only in measuring residual tumor size, but also in missing occult tumor cells. Until the recent 7 th edition of the AJCC Staging System, there were no standardized methods of pathologically measuring residual tumor following NACT. It is not a straightforward task because of the various distribution patterns that can be seen. Relying on radiologic size is not always accurate. Both under and overestimation can occur. For example, if a 5 cm radiologic mass is reduced to a hyalinized, relatively acellular tumor bed which contains two microscopic foci of occult tumor cell clusters measuring 0.2 cm each but separated by 3 cm, how should residual tumor size be interpreted. Is this a 3 cm tumor? Or is this microscopic residual tumor foci, measuring up to 0.2 cm each? (an interpretation that could be substantiated if the intervening 3 cm contains normal proliferative changes without any evidence of stromal changes of tumor regression). The clinical significance of the difference in these interpretations is unknown. AJCC Definition of residual tumor size: AJCC now states that the single largest mass of residual invasive cancer should be measured and used for ypT staging. The background fibrotic tumor bed (granulation tissue, fibrosis, organizing hemorrhage) should not be counted. If there are scattered nests of tumor cells rather than a “mass”, AJCC states that the “largest contiguous area of invasive carcinoma” should be measured. Recommendation: We follow the new AJCC rules, however in many scenarios it is not clear how to apply them. Scenario 1: If there are multiple discrete foci of residual invasive cancer, we base AJCC ypT on the largest discrete focus, but we also document in our report the total span of all invasive foci. Scenario 2: If there is residual invasive cancer but instead of a discrete focus it is present as microscopic cells or clusters distributed in a low cellularity across a large span, we base AJCC ypT on the total span of the invasive cancer. We also give a subjective description of the cellularity (i.e. scant cellularity, low cellularity, high cellularity) to distinguish a 4 cm focus of highly cellular residual cancer from a 4 cm focus of scant residual cancer cells embedded in organizing fibrosis.
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